A ESRP1/circPHGDH/miR-149/RAP1B positive feedback loop promotes the malignant behaviors and glycolysis of prostate...

Circular RNAs are implicated in the pathogenesis of prostate cancer (PCa). However, their functions, biogenesis and molecular mechanisms remain largely elusive. Here we aimed to investigate the role of circPHGDH in PCa. Cellular behaviors were assessed by the colony formation assay, Transwell analysis, western blotting and Seahorse assay. The underlying mechanisms were investigated using a luciferase reporter assay, RNA pull-down and real-time quantitative PCR. The lactylation of ESRP1 was examined by RNA immunoprecipitation, immunoprecipitation and western blotting. Our results revealed that circPHGDH expression was upregulated in PCa tissues and cells. Furthermore, the knockdown of circPHGDH inhibited PCa cell proliferation, migration, invasion, epithelial-mesenchymal transition and glycolysis. Mechanistically, circPHGDH functioned as a sponge for miR-149, which in turn directly targeted RAP1B. The biogenesis of circPHGDH was regulated by the splicing factor ESRP1. The glycolytic product lactate stabilized ESRP1 by promoting its lactylation at the K43 site; conversely, circPHGDH knockdown suppressed ESRP1 lactylation. Moreover, the silencing of circPHGDH inhibited tumor growth and metastasis in vivo via the miR-149/RAP1B axis, whereas circPHGDH facilitated tumor progression. In conclusion, the lactylation-modified ESRP1/circPHGDH/miR-149/RAP1B axis drives the progression of PCa. These findings provide novel insights into the pathogenesis of PCa and suggest promising therapeutic targets for its treatment.